Trimebutine [3,4,5-trimethoxybenzoic acid 2-(dimethylamino)-2-phenylbutylester and its maleate salt] has been used in many countries since 1969 for the treatment of functional bowel disorders, including IBS. The efficacy of trimebutine to relieve abdominal pain has been demonstrated in various clinical studies (see, for example, Ghidini et al (1986) Single drug treatment for irritable colon: Rociverine versus trimebutine maleate. Curr Ther Res 39: 541-548). Trimebutine has proved to be effective in the treatment of both acute and chronic abdominal pain in patients with functional bowel disorders, especially IBS, at doses ranging from 300 to 600 mg/day. It is also effective in children presenting with abdominal pain.
It is thought that the actions of trimebutine on the gastrointestinal tract are mediated in part via (i) an agonist effect on peripheral mu, kappa and delta opiate receptors and (ii) release of gastrointestinal peptides such as motilin and modulation of the release of other peptides, including vasoactive intestinal peptide, gastrin and glucagon. Further, trimebutine accelerates gastric emptying, induces premature phase III of the migrating motor complex in the intestine and modulates the contractile activity of the colon. Recently, trimebutine has also been shown to decrease reflexes induced by distension of the gut lumen in animals to modulate visceral sensitivity.
Nitric oxide (NO) been recently been shown to exert many anti-inflammatory effects, including reduction of leukocyte adherence to the vascular endothelium (Gauthier et al (1994) Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 267: G562-G568) and suppression of production of various chemotactic factors (Walford and Loscalzo (2003) Nitric oxide in vascular biology. J Thromb Haemost 1: 2112-2118). Further, incorporation of an NO-releasing moiety into certain drugs such as NSAIDs, acetaminophen and ursodexycholic acid has been shown to enhance activities of these drugs and reduce toxicity relative to the parent drug.
Hydrogen sulfide (H2S) is another type of gaseous mediator that may exert anti-inflammatory effects Recently it has been shown that H2S releasing agents exhibit analgesic activity in models of visceral pain (Distrutti et al (2005) Evidence that hydrogen sulfide exerts antinociceptive effects in the gastrointestinal tract by activating KATP channels. J Pharmacol Exp Ther 316: 325-335. Further, H2S has been shown to be a smooth muscle relaxant in intestinal tissues (see Teague, B. et al. (2002) The Smooth Muscle Relaxant effect of Hydrogen Sulfide In Vitro: Evidence for a Physiological Role to Control Intestinal Contractility. Br. J. Pharmacol. 137: 139-145.
The inventors have shown in the present application that the activity of trimebutine is significantly enhanced when salts of trimebutine or N-monodesmethyl trimebutine and their corresponding stereoisomers are formed with various NO-releasing, H2S-releasing or combined NO— and H2S-releasing moieties. In particular, administration of these NO-releasing, H2S-releasing or combined NO— and H2S-releasing salts of trimebutine and N-monodesmethyl trimebutine results in improved analgesic properties when compared to trimebutine (trimebutine maleate) or its metabolite N-monodesmethyl trimebutine alone and when compared to the NO-releasing, H2S-releasing or combined NO— and H2S-releasing moiety alone. These salts are particularly useful in the treatment of conditions characterized by abdominal pain such as such as irritable bowel syndrome, inflammatory bowel disease, diabetic gastroparesis, dyspepsia and the like.